The goal of this project is to understand why HCV infection fails to induce a strong cell mediated immune responsible to eliminate the virus. Here we propose to investigate relevant immune parameters in a small animal model and in vitro. Because HCV is not infectious in mice, models making use of HCV transgenic mice, animals infected with adenovirus constructs coding for an HCV gene and in vitro culture systems will be used. In the previous granting period we have established experimental approaches to study immune responses in the liver with the aim to elucidate how HCV gene modulate these responses Because the HCV core to date is the only HCV coded protein with putative immunoregulatory functions we are focusing on the immunoregulatory effects of this protein. The HCV core has been reported to exert a multitude of effects, namely on TNFalpha and Fas signaling the induction of cytotoxic T cells and the induction of IL-12. The availability of HCV core transgenic mice and adenoviral vectors expressing the HCV core, both generated in the previous granting period make it possible to investigate whether the core period has immunoregulatory effects. Specifically we will examine how the HCV core modulates signaling through TNF receptors. We will examine what are the effects of the core on the induction of cytotoxic T cells in vivo and in vitro. Given the notion that the core has effects on IL-12 we will explore its influence on the maturation and function of antigen presenting cells in the liver. Because there is increasing evidence for an important role of NK cells in viral liver infections we will elucidate whether the core has effects on the function of these cells during a virus infection.